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PMID:20086093

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Citation

Lin, Q, Wang, J, Childress, C, Sudol, M, Carey, DJ and Yang, W (2010) HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK. Mol. Cell. Biol. 30:1541-54

Abstract

ACK (activated Cdc42-associated tyrosine kinase) (also Tnk2) is an ubiquitin-binding protein and plays an important role in ligand-induced and ubiquitination-mediated degradation of epidermal growth factor receptor (EGFR). Here we report that ACK is ubiquitinated by HECT E3 ubiquitin ligase Nedd4-1 and degraded along with EGFR in response to EGF stimulation. ACK interacts with Nedd4-1 through a conserved PPXY WW-binding motif. The WW3 domain in Nedd4-1 is critical for binding to ACK. Although ACK binds to both Nedd4-1 and Nedd4-2 (also Nedd4L), Nedd4-1 is the E3 ubiquitin ligase for ubiquitination of ACK in cells. Interestingly, deletion of the sterile alpha motif (SAM) domain at the N terminus dramatically reduced the ubiquitination of ACK by Nedd4-1, while deletion of the Uba domain dramatically enhanced the ubiquitination. Use of proteasomal and lysosomal inhibitors demonstrated that EGF-induced ACK degradation is processed by lysosomes, not proteasomes. RNA interference (RNAi) knockdown of Nedd4-1, not Nedd4-2, inhibited degradation of both EGFR and ACK, and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF-induced degradation of EGFR. Our findings suggest an essential role of Nedd4-1 in regulation of EGFR degradation through interaction with and ubiquitination of ACK.

Links

PubMed PMC2832494 Online version:10.1128/MCB.00013-10

Keywords

Amino Acid Motifs; Amino Acid Sequence; Animals; Cell Line; Conserved Sequence; Endosomal Sorting Complexes Required for Transport/chemistry; Endosomal Sorting Complexes Required for Transport/metabolism; Epidermal Growth Factor/pharmacology; Gene Knockdown Techniques; Humans; Lysosomes/drug effects; Lysosomes/metabolism; Mice; Molecular Sequence Data; Mutant Proteins/metabolism; Proteasome Endopeptidase Complex/drug effects; Proteasome Endopeptidase Complex/metabolism; Protein Binding/drug effects; Protein Processing, Post-Translational/drug effects; Protein Structure, Tertiary; Protein-Tyrosine Kinases/chemistry; Protein-Tyrosine Kinases/metabolism; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction/drug effects; Ubiquitin-Protein Ligases/chemistry; Ubiquitin-Protein Ligases/metabolism; Ubiquitination/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ACK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96PU5

F

Seeded From UniProt

complete

MOUSE:ACK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46934

F

Seeded From UniProt

complete

MOUSE:ACK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62993

F

Seeded From UniProt

complete

MOUSE:ACK1

enables

GO:0050699: WW domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46934

F

Seeded From UniProt

complete

HUMAN:NEDD4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54967

F

Seeded From UniProt

complete

HUMAN:NEDD4

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:Q07912)

Seeded From UniProt

complete

HUMAN:GRB2

part_of

GO:0070436: Grb2-EGFR complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GRB2

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54967

F

Seeded From UniProt

complete

HUMAN:ACK1

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ACK1

part_of

GO:0070436: Grb2-EGFR complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O54967

F

Seeded From UniProt

complete

HUMAN:NEDD4

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(UniProtKB:Q07912)

Seeded From UniProt

complete

HUMAN:NEDD4

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NEDD4

involved_in

GO:0043162: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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